Acylamido-hydroxy-propionaphthones



Patented Mar. 13, 1951 ACYLAMIDO-HYDROXY-PROPIO- NAPHTHONES Loren M. Long, Grosse Pointe Woods, and Harvey D. Troutman, Ferndale, Mich., assignors to Parke, Davis & Company, Detroit, Mich., a cor-' poration of Michigan No Drawing. Application January 21, 1950, Serial No. 139,955

7 Claims.

This application is a continuation in part of our co-pending application, Serial Number 83,770, filed March 26, 1949, now U. S. Patent 2,516,130, and the invention relates to new keto amido alcohols and to chemical methods useful for their synthesis. More particularly, the invention relates to naphthyl a-acylamido- ,B-hydroxyethyl ketone compounds having the formula,

O NHAcyl where n is l or 2, and R is the same or different and represents hydrogen, halogen, nitro, lower alkyl, or lower alkoxy radicals. The term acyl as used herein includes such acyl radicals as saturated and unsaturated lower aliphatic acyl, halogen substituted lower aliphatic acyl, carboxy substituted lower aliphatic acyl, cyano substituted lower aliphatic acyl, ether substituted lower aliphatic acyl," ester substituted lower aliphatic acyl, hydroxy substituted lower aliphatic acyl, benzoyl, substituted benzoyl, araliphatic acyl, furoyl, pyridinoyl and the like radicals.

In accordance with the invention, naphthyl a-acylamido-fl-hydroxyethyl ketone compounds having the above formula are obtained by condensing a naphthyl acylamidomethyl ketone of formula,

alkaline O condensation catalyst H o-onuvrmm where F. and n have the same significance as given above.

In carrying out this condensation, the formaldehyde may be supplied to the reaction mixture in a number of different forms. For example, formaldehyde gas, aqueous or alcoholic solutions of formaldehyde, paraformaldehyde and other formaldehyde-yielding polymers may I be used. In most cases it has been found preferable to use an excess of formaldehyde, usually up to about four or five moles, in order to insure completeness of the condensation reaction.

A variety of solvents, alkaline condensation catalysts, and reaction conditions may also be employed. As solvents, either aqueous or anhydrous lower aliphatic alcohols are particularly advantageous, but moist dialkyl ethers and dioxanewater mixtures may also be used. The alkaline condensation catalysts used in. this phase of the invention may be organic bases, inorganic bases, or inorganic salts of acidic or pseudo acidic organic compounds. Some representative types of these catalysts are the hydroxides, oxides, carbonates, bicarbonates, and amides of alkali or alkali earth metals, alkali metal alkoxides, alkali earth alkoxides, alkali metal phenolates, alkali metal salts of lower aliphatic carboxylic acids, organic tertiary amines and quaternary ammonium hydroxides of organic tertiary amines. In general, the weakly alkaline catalysts, such as sodium bicarbonate, potassium bicarbonate, calcium hydroxide, pyridine, triethyl amine, N- ethyl morpholine, N,N-dimethyl aniline, and the like are preferred. They make the reaction much easier to control. When strongly alkaline catalysts, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium 'methylate, sodium ethylate, and the like are used, care must be taken to remove or inactivate the catalyst as soon as the reaction is completed in order to prevent conversion of the desired product to the corresponding methylene bis compound by dehydration and coupling reaction. Although the amount of catalyst is not critical and can vary froma few hundredths or thousandths of a mole to one mole or more, it is preferable from the standpoint of yield to use only enough to bring about a relativelyrapid reaction In most" and usually requires from 15 minutes to several hours at room temperature or slightly above, that is at about 25-50 C. a t t The products of the invention are useful as intermediates in the preparation of other organic compounds. They are of particular value in preparation of organic compounds possessing unique antibiotic activity.

The invention is illustrated by the following examples:

Example 1 is collectedand purifiedby recrystallization from ethyl acetate.

Example 2 50 g. of 4-methoxy-2-naphthyl phenylacetamidomethyl ketone is mixed with 12 g. of paraformaldehyde in 1 liter of methanol. The resulting mixture is treated with 0.4 g. of sodium bicarbonate and heated at 40 C. for about twenty minutes with stirring. 3 liters of ice water are added and the crude 4-methoxy-2-naphthyl a-phenylacetamido-;3-hydroxyethy1 ketone which separates collected, washed with water and purifled by recrystallization from alcohol. The formula of this product is:

- n-omon oer,

Example 3 A mixture consisting of 50 g. 4-nitro-1- naphthyl acetamidomethyl ketone and 75 cc. of 40% formalin in 450 .cc. of methanol istreated with-2 g. of sodium bicarbonate and the-resulting mixture heated at 45 C. for about one-half hour. The reaction mixture is pouredinto l and onehalf liters of ice water and the crude l-nitro-lnaphthyl e-acetamido ,6 hydroxyethyl ketone which separates collected and washed with water. If desired, this product can be purified by recrystallization from methanol. Its formula-is,

NO: I

llkramplev 4 A mixture consisting of 62 g. of 6-methyl-2- naphthyl p-toluylamidomethyl ketone, .300 cc. of methanol and '75 cc. of 40% formalin is treated with 2 g. of potassium bicarbonate. The mixture is stirred at 35 C. for about one and one-half 4. hours, cooled and the insoluble 6-methy1-2- .naphthyl e-(p-toluylamido) -p-hydroxyethyl ketone collected. This product is Washed with water and dried in vacuo. Its formula is,

Y GE's- Example 5 .A mixture consisting of 50 g. of 8-nitro-lnaphthyl acetamidomethyl ketone in cc. of 40% formalin .in 450 cc. of-methanol is treated with 2 g. of sodium bicarbonate and the resulting mixture heated at 45 C. for about one-half hour. The reaction mixture is poured into one and onehalf liters of ice water and the crude 8-nitro-1- naphthyl a-acetamido e-hydroxyethyl ketone which separates is collected and washed with water. If desired this product can be purified by recrystallization from methanol. Its formula is,

II OgN o-rm-omon Example 6 A mixture of 5.0 g. of 1-nitro-2-naphthyl acetamidomethyl ketone in 75 cc. of 40% formalin in 450 cc. of methanol is treated with 2 g. of sodium bicarbonate and the resulting mixture heated at 45 C. for about one-half hour. The reaction mixture is poured into one and one-half liters of ice water and the crude l-nitro-Z-naphthyl e-acetamido-fi-hydroxyethyl ketone which separates is collected and washed with water. This product can be purified by recrystallization from methanol. Its formula is,

Example 7 A mixture consisting of 65 g. of 2,4-dimethyl-lnaphthyl p-toluylamidomethyl ketone, 300 cc. of methanol and 75 cc. of 40% formalin is treated with 2 g. of potassium bicarbonate. The mixture is stirred at 35 C. for about one and onehalf hours, cooled and the insoluble 2,4-dimethyl-l-naphthyl a-(p-tolllYIEIIlidO) -c-hydroxyethyl ketone collected. This product is washed with water and dried in vacuo. Its formula is,

O NH-HI-O-CH! 0 mula is Example 9 53 g. of 4-iodo-1-naphthy1 benzamidomethyl ketone is mixed with 12 g. of paraformaldehyde in one liter of methanol. The resulting mixture is treated with 4.5 g. of sodium bicarbonate and heated at 40 C. for about minutes with stirring. 3 liters of ice water are added and the crude 4-iodo-1-naphthyl a-benzamido-c-hydroxyethyl ketone which separates is collected,'

Washed with water, and purified by recrystallization from alcohol. The formula of thi product O 0 I l t t-cryonics! Example 10 52 g. of 6-bromo-2-naphthyl benzamidomethyl ketone is mixed with 12 g. of paraformaldehyde in one liter of methanol. The resulting mixture is treated with 0.4 g. of potassium bicarbonate and heated at 37 C. for about twenty minutes with stirring. 3 liters of ice water are added and the crude 6-bromo-2-naphthy1 c-benzamido-flhydroxyethyl ketone which separates is collected, washed with water and purified by recrystallization from alcohol. The formula of this product Example 11 62 g. of l-naphthyl crotonylamidomethyl ketone is mixed with 325 cc. of methanol and '75 cc. of 40% formalin, 2 g. of potassium bicarbonate is added and the mixture stirred at room temperature for about one hour during which time the desired product separates. The insoluble 1- 6 naphthyl a-crotonylamido-fi-hydroxyethyl ketone of formula,

is collected and purified by recrystallization from ethyl acetate.

Example 12 45 g. of 5-ethyl-1-naphthyl bromoacetamidomethyl ketone is mixed with 12 g. of paraformaldehyde in 1 liter of methanol. The resulting mixture is treated with 0.4 g. of sodium bicarbonate and heated at 35 C. for about 20 minutes with stirring. 3 liters of ice water are added and the crude 5-ethyl-1-naphthyl a-bromoacetamidop-hydroxyethyl ketone which separates is collected, washed with water and purified by recrystallization from ethanol. The formula of this product is,

Example 13 65 g. of 4-nitro-1-naphthyl dichloroacetamidomethyl ketone is mixed with 350 cc. of methanol in 75 cc. of 40% formalin. 2 g. of sodium bicarbonate is added and the mixture is stirred at room temperature for about 1 hour during which time the desired product separates. The insoluble 4-nitro-l-naphthyl a-dichloroacetamido ,8 hydroxyethyl ketone of formula,

is collected and purified by recrystallization from ethyl acetate.

Example 1-4 48 g. of 4-ethoxy-1-naphthy1succinamidomethyl ketone is mixed with 12 g. of paraformaldehyde and 1 liter of methanol. The resulting mixture is treated with 0.4 g. of sodium bicarbonate and heated at 40 C. for twenty minutes with stirring. Two and one-half liters of ice water ar added and the crude 4-ethoxy-l-naphthyl a-SIICCil'lamido-p-hydroxyethyl ketone which separates is collected, washed with water and purified by' reanew crystallization fromalcohol. The formula of this productis,

CnHs

Emample 15 '70 g. of 8-chloro-1-naphthyl cyanoacetamidomethyl ketone is mixed with 350 cc. of methanol and 75 cc. of 40% formalin. 2.2 g. of potassium bicarbonate is added and the mixture is stirred at room temperature for about 1 hour during which time the desired product separates. The insoluble 8-chloro-l-naphthyl a-cyanoacetamidofi-hydroxyethyl ketone of formula,

C NH-i-GHaCN is collected and purified by recrystallization from ethyl acetate.

Example 1 6 65 g. of l-naphthyl p-methoxypropionamidomethyl ketone is mixed with 300 cc. of methanol and '75 cc. of 40% formalin. 2 g. of sodium bicarbonate is added and the mixture stirred at room temperature for about one hour during which time the desired product separates. The solid is collected and purified by recrystallization from alcohol. The formula of this-product is,

O (I? NlEiF-lk-CHPCHIO CH3 C- H-OH2OH Example 17 65 g. of l-naphthyl acetoxyacetamidomethyl ketone is mixed with 350 cc. of methanol and '75 cc. of 40% formalin. 2.3 g. of potassium bicarbonate is added and the mixture is stirred at room temperature for about one hour anda half during which time the desired product separates. The insoluble l-naphthyl a-acetoxyacetamido-fi-hydroxyethyl ketone of formula,

is collected and purified by recrystallization from ethylacetate.

Example 18 A mixture consisting of 6.0 g. of '7-ethyl-lnaphthyl furamidomethyl ketone, 30 cc. of methanoland 7.5 cc. of 40% formalin is treated with 8 0.2 g. of potassium bicarbonate. The mixture is stirred at 35 C. for about one and one-half hours, cooled and the insoluble 7-ethyl-l-naphthyl a-furamido-p-hydroxyethyl ketone collected. This product is washed with Water and dn'ed in vacuo. It formula is,

R NEH! 0 I 0 Example 19 v 48 g. of 'F-chloro-l-naphthyl a-nicotinamidomethyl ketone, 280 cc. of methanol and 70 cc. of 40% formalin is treated with 1.8 g. of sodium bicarbonate. The mixture is stirred at 35 C. for about one and one-quarter hours, cooled and the insoluble 7-chloro-1-naphthyl a-nicotinamido- B-hydroxyethyl ketone collected. Thi product is washed with water and dried in vacuo. Its formula is,

o H NEE-C i .L ('3- rc-omon Example 20 Example 21 A mixture consisting of 21 g. of 4-nitro-1- naphthyl fiuoroacetamidomethyl ketone and 40 cc. of 40% formalin in 250 cc. of methanol is treated with 1.2 g. of potassium bicarbonate and the resulting mixture heated at 40 C. for about three-quarters of an hour. The reaction mixture is poured into one liter of ice water and the 4-nitro-l-naphthyl a-fiuoroacetamido-,6-hydroxyethyl ketone which separates is collected and washed with water. This product can be recrystallized from methanol. Its formula is,

ll NH-C-CHzF The naphthyl acylamidomethyl ketone compounds used as starting materials in the ractice of the invention can be prepared by the reaction of a naphthyl w-halomethyl ketone with hexamethylenetetramine, hydrolysis of the resulting complex with mineral acids followed by simultaneous neutralization and acylation of the naphthylamidomethyl ketone acid addition salts. For example, l-naphthyl acetamidomethyl ketone, starting material used in Example 1, can be prepared as follows:

150 g. of hexamethylenetetramine dissolved in chloroform is added to 220 g. of l-naphthyl bromomethyl ketone and the mixture allowed to stand at room temperature for about three hours. The 1-naphthyl bromomethyl ketone-hexamethylenetetramine complex is collected, washed with a little chloroform and dried. The formula of this product is.

200 g. of l-naphthyl bromomethyl ketone hexamethylenetetramine complex is added to 225 cc. of concentrated hydrochloric acid and 1200 cc.

of absolute ethanol and the mixture is stirred overnight at room temperature. The insoluble hydrochloride salt of l-naphthyl aminomethyl ketone is collected by filtration, washed with a small amount of cold water, and dried at room temperature. The formula of this product is,

O -CHRNHI-HCI 75 g. of l-naphthyl aminomethyl ketone hydrochloride is dissolved in 500 cc. of glacial acetic acid and 300 cc. of acetic anhydride. g. of sodium acetate is added in small portions with stirring and after the addition has been completed, the solution is diluted with water. 1- naphthyl acetamidomethyl ketone which separates is collected and recrystallized from methanol. The formula of this products is,

What we claim is: 1. A compound of formula,

0 NHAcyl "lit where n is one of the integers 1 and 2 and R is a member of the class consisting of hydrogen,

halogen, nitro, lower alkyl and lower alkoxy radicals.

2. A compound of formula,

0 NHAcyl H-CHaOH 3. 1 naphthyl a acetamido B hydroxyethyl ketone.

4. A compound of formula,

0 NHAcyl H-C H: OH

LOREN M. LONG.

HARVEY D. TROU'ITMAN.

a. fluoroacet- No references cited. 

1. A COMPOUND OF FORMULA, 